Entry
Periodontal Regeneration
Leonardo Mancini * , Adriano Fratini and Enrico Marchetti






Citation: Mancini, L.; Fratini, A.;
Marchetti, E. Periodontal
Regeneration. Encyclopedia 2021, 1,
87–98. https://doi.org/10.3390/
encyclopedia1010011
Academic Editor: Samir Nammour
Received: 30 October 2020
Accepted: 11 January 2021
Published: 13 January 2021
Publisher’s Note: MDPI stays neu-
tral with regard to jurisdictional clai-
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nal affiliations.
Copyright: © 2021 by the authors. Li-
censee MDPI, Basel, Switzerland.
This article is an open access article
distributed under the terms and con-
ditions of the Creative Commons At-
tribution (CC BY) license (https://
creativecommons.org/licenses/by/
4.0/).
Encyclopedia 2021, 1, 87–98. https://doi.org/10.3390/encyclopedia1010011
Department of Life, Health and Environmental Sciences, University of L’Aquila, 67100 L’Aquila, Italy;
adriano.fratini@graduate.univaq.it (A.F.); enrico.marchetti@univaq.it (E.M.)
* Correspondence: mancinileonardo94@gmail.com
Definition: Periodontal regeneration is a technique that aims to regenerate the damaged tissue
around periodontally compromised teeth. The regenerative process aims to use scaffolds, cells, and
growth factors to enhance biological activity.
Keywords: periodontal regeneration; GTR; biomaterials; growth factors; biologics; periodontitis
1. Introduction and History
Periodontitis is a multifactorial disease characterized by microbially-associated, host-
mediated inflammation that results in loss of periodontal attachment, eventually leading
to tooth loss [1]. Periodontitis is the sixth most prevalent disease for mankind [2] and is a
public health problem since it is so widely prevalent, causes disability [3], and numerous
clinical and experimental studies have shown the presence of an association between
periodontitis and some systemic diseases, in particular cardiovascular diseases, diabetes,
lung diseases, and pregnancy complications [4,5]. The goal of periodontal therapy is
to arrest progressive attachment loss, through the control of infection, to prevent tooth
loss [6]. Probing pocket depth reduction as a surrogate outcome variable is validated by
data demonstrating lower risk for disease progression and tooth loss [7,8] associated with
the absence of bleeding on probing [9,10]. Periodontal pockets related to intraosseous
defects often remain after nonsurgical treatment and could increase risk of progressive
periodontitis [11,12] and, as such, are often considered to require surgical intervention.
Based on the studies of Melcher (1976) [13], who developed the concept of using barrier
membranes to “guide” the biological process of wound healing, in the mid-1980s clinical
reports showed that intraosseous defects have potential for healing through regeneration
using barrier membranes [14,15]. Today we know which bio-clinical principles regulate
periodontal regeneration: wound stability, space provision, and primary intention heal-
ing [16]. Many randomized controlled trials and systematic reviews have shown that
periodontal regenerative therapies can achieve better treatment outcomes compared to
open flap debridement in the treatment of angular defects [17–19]. Several techniques and
biomaterials have been studied for periodontal regeneration of intraosseous defects, but
from a histological and clinical point of view, guided tissue regeneration (GTR), enamel
matrix derivatives (EMD), and decalcified freeze-dried bone allograft (DFDBA) are the
most effective approaches to periodontal regeneration [20–24]. A recent consensus report
of the American Academy of Periodontology recommended surgical intervention as the
treatment of choice for intraosseous defects [25].
2. Techniques
Membrane exposure resulting in bacterial contamination during healing has been
the major complication of regenerative procedures in the past, with a prevalence in the
range of 50–100% [26,27]. Cortellini et al. [28] reported that the prevalence of membrane
exposure could be significantly reduced with the use of access flaps specifically designed to
preserve interdental tissues (the modified papilla preservation technique). The first papilla
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preserve interdental
preserve tissues (the tissues
interdental modified(thepapilla preservation
modified technique). The
papilla preservation first pa-The first pa-
technique).
preservation technique was described by Takey et al. 1985 [29] and is used to prevent soft
pilla preservation
pilla technique was
preservation described
technique wasbydescribed
Takey et al.
by 1985
Takey[29]
et and1985
al. is used
[29] to prevent
and is used to
tissue collapse and to maintain stability during the regeneration phase (Figure 1).prevent
soft tissue collapse and to maintain stability during the regeneration phase (Figure 1).
soft tissue collapse and to maintain stability during the regeneration phase (Figure 1).

FigureFigure
1. Illustration
1.Figure ofIllustration
1. theof
Illustration papilla preservation
the papilla
of papilla flap
the preservation according to Takey
flap according
preservation flap et alto
to Takey
according 1985.
etTakey
al. 1985.
et al 1985.

In general, the
In development
In general,
general,the of new procedures
the development
development newhas
ofnew
of been aimed
procedures
procedures at
hasbeen
has beencomplete
aimedat
aimed preser-
atcomplete
completepreser-
preser-
vation
vation of thevation of the
marginal
of the marginal
tissue tissue
in order
marginal in order
order
to obtain
tissue in andtomaintain
to obtain and
obtain and maintain
a primary
maintain aa primary
primary
closure aboveclosure above the
the above
closure the
applied
applied regenerative regenerative
material material
during the during
critical the
phasescritical
of phases
healing. of healing.
Specifically,
applied regenerative material during the critical phases of healing. Specifically, the flapSpecifically,
the flap the flap
designs
designs sought soughtpassive
to achieve
designs sought to achieve
to achieve passive
primary
passive primary
closure
primary closure
of the of the
the flap
flap combined
closure of flapwith
combined with excellent
excellent
combined with excellent
wound
wound stability. stability.
Today, Today, papilla-preserving
papilla-preserving flap designsflap
anddesigns
flap and
closure flap closure
techniques
wound stability. Today, papilla-preserving flap designs and flap closure techniques techniques
are are are
the
standard
the standardthe
approach approach
for for
regenerativeregenerative
periodontalperiodontal
surgery surgery
(Figure
standard approach for regenerative periodontal surgery (Figure 2). (Figure
2). 2).

Figure 2. Illustration
Figure 2.ofIllustration
flap designof
for periodontal
flap design forregeneration.
periodontal regeneration.
Figure 2. Illustration of flap design for periodontal regeneration.
Encyclopedia
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The
TheModified
ModifiedPapillaPapillaPreservation
Preservation(MPPT) (MPPT)technique
techniquewas wasdeveloped
developedto toincrease
increasethe the
space for regeneration and to achieve and maintain primary
space for regeneration and to achieve and maintain primary flap closure in the flap closure in the interdental
interden-
space [30].[30].
tal space MPPT allows
MPPT primary
allows closure
primary of theofinterdental
closure the interdental space,space,
resulting in better
resulting pro-
in better
tection of the membrane from the oral environment [28].
protection of the membrane from the oral environment [28]. MMPT can be successfully MMPT can be successfully ap-
plied at sites
applied where
at sites the interdental
where the interdental spacespace
widthwidthis at least
is at2 mm
leastin2 the
mmmost in the coronal
most portion
coronal
of the papilla. When the interdental sites are narrower, a different
portion of the papilla. When the interdental sites are narrower, a different papilla preser- papilla preservation
procedure (the simplified
vation procedure papilla preservation
(the simplified flap, SPPF)
papilla preservation flap,has been
SPPF) hasproposed [31]. In [31].
been proposed the
latter study, it was possible to close 100% of the narrow interdental
In the latter study, it was possible to close 100% of the narrow interdental papillae over papillae over resorb-
able membranes
resorbable and 67%
membranes andmaintained
67% maintained primary closure
primary over over
closure time,time,
resulting in clinical
resulting at-
in clinical
tachment
attachment gains
gainsof 4.9 ± 1.8
of 4.9 ± mm.
1.8 mm.In order to further
In order preserve
to further preservewoundwound stability and and
stability furtherfur-
limit
ther morbidity,
limit morbidity, a papilla-preserving
a papilla-preserving flap can flapbecan
usedbein usedthe in
context of a minimally
the context of a minimallyinva-
sive surgical
invasive technique
surgical technique associated
associatedwith withhigh-powered
high-powered magnification
magnificationsystems systems[32].[32].TheThe
minimally
minimally invasive approaches (MIST, M-MIST) are particularly suitable in the caseof
invasive approaches (MIST, M-MIST) are particularly suitable in the case of
therapies
therapiesthat thatinvolve
involvethe theuse
useofofbiologically
biologicallyactiveactiveagents
agentssuch suchasasEMDEMDororgrowth growthfactors.
factors.
The
Theinterdental
interdentalpapilla papillaassociated
associatedwith withthethedefect
defectisismade
madeaccessible
accessibleusing usingthe theSimplified
Simplified
Papilla
PapillaPreserving
PreservingFlap Flap(SPPF)
(SPPF)or orModified
Modified Papilla
Papilla Preservation
Preservation (MPPT) (MPPT) technique.
technique. All All
surgical
surgicalprocedures
proceduresare areperformed
performedwith withthe theaidaidofofaamicroscope
microscopeor oraamagnification
magnificationsystem system
(4X–16X)and
(4X–16X) andmicrosurgical
microsurgicalinstruments
instruments[33]. [33].AAfurther
furtherdevelopment
developmentin inthe
themicrosurgical
microsurgical
field was the single flap approach [34,35]. This therapeutic strategy, which isislimited
field was the single flap approach [34,35]. This therapeutic strategy, which limitedto to
reconstructive surgery of intraosseous defects, involves the dissection
reconstructive surgery of intraosseous defects, involves the dissection of a mucoperios- of a mucoperiosteum
flap from
teum flap afrom
single side (exclusively
a single vestibular
side (exclusively or exclusively
vestibular lingual/palatal).
or exclusively The applica-
lingual/palatal). The
tion of the SFA
application of theis indicated only when
SFA is indicated onlythe extension
when of the intraosseous
the extension defect is prevalent
of the intraosseous defect is
from the from
prevalent buccalthe or buccal
lingual/palatal side and side
or lingual/palatal accessand from onefrom
access side one
onlyside allowsonly adequate
allows
surgical cleansing of the intraosseous lesion and the radiological
adequate surgical cleansing of the intraosseous lesion and the radiological surface affected surface affected by the
defect. Aslan et al. proposed a novel surgical approach, the
by the defect. Aslan et al. proposed a novel surgical approach, the ‘‘entire papilla preser-“entire papilla preservation
(EPP)”(EPP)’’
vation technique, for regenerative
technique, for regenerative treatment of isolated
treatment deepdeep
of isolated intraosseous
intraosseous defects [36].
defects
[36]. This novel concept provides an intact gingival space over the intraosseous defect,a
This novel concept provides an intact gingival space over the intraosseous defect, with
completely
with a completelypreserved interdental
preserved papilla.
interdental A one-year
papilla. A one-yearprospective cohort
prospective study
cohort [37] with
study [37]
12 isolated deep non-contained intraosseous defects treated
with 12 isolated deep non-contained intraosseous defects treated with a combination of with a combination of EMD
and deproteinized
EMD and deproteinized bovine bone mineral
bovine bone mineralshowed 100% primary
showed 100% primaryclosureclosure
during during
the healingthe
period and resulted in 6.83 mm of average clinical
healing period and resulted in 6.83 mm of average clinical attachment gain.attachment gain.

3. Materials
3. Materials
Several studies have investigated the use of biomaterials and biologics in periodontal
Several studies have investigated the use of biomaterials and biologics in periodontal
regeneration [38–40]. Various products are currently available on the market, including
regeneration [38–40]. Various products are currently available on the market, including
bone grafts, bone fillers, scaffolds, membranes, and growth factors (Figure 3).
bone grafts, bone fillers, scaffolds, membranes, and growth factors (Figure 3).

Figure
Figure3.3.Illustration
Illustrationofofmaterials
materialsfor
forperiodontal
periodontalregeneration.
regeneration.

3.1. Grafts and Fillers

Autogenous, allogeneic, xenogeneic bone substitutes, and synthetic materials are re-
ferred to as bone fillers, due to their capacity to narrow the gap of the periodontal defect.
 Encyclopedia 2021, 1 90

pedia 2021, 1, FOR PEER REVIEW 3.1. Grafts and Fillers 4

Autogenous, allogeneic, xenogeneic bone substitutes, and synthetic materials are

referred to as bone fillers, due to their capacity to narrow the gap of the periodontal defect.
Osteoconduction, osteogenesis, and
Osteoconduction, osteoinduction
osteogenesis, are the characteristics
and osteoinduction that enable cells
are the characteristics that enable cells
to move in thetodefect,
moveandin the to defect,
generate and and
to induce
generate theand
chemotaxis
induce the ofchemotaxis
other cells [41]. Not cells [41]. Not
of other
all of these properties
all of theseareproperties
related to are eachrelated
biomaterial;
to eachhowever,
biomaterial;osteoconduction is the
however, osteoconduction is the
most common property for bone fillers. According
most common property for bone fillers. According to Bosshardt and Sculean 2009 [42], the to Bosshardt and Sculean 2009 [42],
the evaluation
evaluation of biomaterials of biomaterials
in periodontal in periodontal
regeneration should regeneration
be histological should be than
rather histological rather
clinical, as thethan clinical,
re-entry as the re-entry
radiographs radiographs
in several in several cases
cases demonstrate demonstrate
an impressive an impressive vol-
volume
gain. Indeed, aume gain. Indeed,
histological analysisa histological
might revealanalysis mightpresence
the possible reveal the possibleencap-
of fibrous presence of fibrous
sulation around encapsulation
bone grafts and around
a small bone grafts
portion ofand a small
the newly portion
formed of the
bone newly
in the formed bone in the
proximity
of pre-existing bone without any actual regeneration. Bovine xenografts, as opposed toxenografts, as
proximity of pre-existing bone without any actual regeneration. Bovine
biphasic calciumopposed to biphasic
phosphate calcium phosphate
and bioactive glass, show andunusual
bioactivefibrous
glass, show unusual fibrous encap-
encapsulation
sulation [40,43,44]. Periodontal regeneration consists of
[40,43,44]. Periodontal regeneration consists of the restoration of connective tissue attach- the restoration of connective tissue
attachmentperiodontal
ment (CTA), cementum (CTA), cementum ligament, periodontal
and proper ligament, and proper
bone. Evidence bone.CTA
for new Evidence for new
remains limited CTA andremains
autogenouslimitedbone and autogenous
showed bone showed
incomplete incomplete
regeneration with aregeneration
long junc- with a long
junctional
tional epithelium epithelium
and little new CTAand [45];little
other new CTA [45]; other
considerations considerations
are the presence of aare the presence of
sec-
a second surgical site and patient morbidity, which
ond surgical site and patient morbidity, which may hinder clinical procedures. The data may hinder clinical procedures. The
data on bone allografts are controversial; indeed, donor
on bone allografts are controversial; indeed, donor age and the site of origin might affect age and the site of origin might
the regenerativeaffect the regenerative
potential potentialevaluation
[46]. A histological [46]. A histological
revealed the evaluation
presencerevealed
of a long the presence of
junctional epithelium [47]. Regarding the demineralized freeze-dried allografts at the con- allografts at
a long junctional epithelium [47]. Regarding the demineralized freeze-dried
the contrary
trary to the freeze-dried to the freeze-dried
allografts showed an evident allografts andshowed an evident
histologic periodontaland regener-
histologic periodontal
regeneration [20]. However, in several countries
ation [20]. However, in several countries in the European Union, regulations do not in the European Union,
allowregulations do
not allow the use of these types of material. Xenografts
the use of these types of material. Xenografts and allogenic grafts showed a moderate and allogenic grafts showed a
moderate periodontal regeneration with some new CTA; the CTA gain might be related
periodontal regeneration with some new CTA; the CTA gain might be related to the use
to the use of membranes as barriers; indeed, encapsulation is recurrent for these types of
of membranes as barriers; indeed, encapsulation is recurrent for these types of filler (Fig-
filler (Figure 4) [48]. The disadvantage of these materials is the inability to regenerate and
ure 4) [48]. The disadvantage of these materials is the inability to regenerate and restore
restore the CTA. Thus, using these materials is more suitable for a bone regeneration, and
the CTA. Thus, using these materials is more suitable for a bone regeneration, and they
they are therefore commonly used in guided bone regeneration (GBR) [49].
are therefore commonly used in guided bone regeneration (GBR) [49].

Figure 4. (A) Xenogeneic collagenated bone graft; (B) xenogeneic graft in particles.
Figure 4. (A) Xenogeneic collagenated bone graft; (B) xenogeneic graft in particles.

3.2. Membranes
3.2. Membranes
Membranes have been used since the introduction of the GTR concept [14,15]. As
Membranes have been used since the introduction of the GTR concept [14,15]. As
mentioned earlier, the principal aim is to select and isolate cells that are able to restore the
mentioned earlier, the principal aim is to select and isolate cells that are able to restore
periodontal ligament, cementum, and connective tissue. Guiding cells in the periodontal
the periodontal ligament, cementum, and connective tissue. Guiding cells in the peri-
defect is the primary target and this is possible through the exclusion of epithelial cells,
which have a fast turnover compared to osteoblasts and fibroblasts [50]. The ideal mem-
brane should respect several principles:
Encyclopedia 2021, 1 91

odontal defect is the primary target and this is possible through the exclusion of epithelial
cells, which have a fast turnover compared to osteoblasts and fibroblasts [50]. The ideal
membrane should respect several principles:
• Biocompatibility: the membrane should not activate an immune response or an acute
inflammation, which may worsen the regenerative phase.
• Cell-exclusion: it should act as a barrier and exclude specific types of cells.
• Tissue integration: it should prevent the down-growth of epithelial cells and the
encapsulation of the material.
• Space-making: it should create and maintain space adjacent to the root surface, allow-
ing the ingrowth of tissue from the periodontal ligament.
• Clinical handling: it should be easy to handle.
There are several membranes on the market (Table 1):

Table 1. Classification of membranes for guided tissue regeneration (GTR).

Class Material Description Commercial Name

Mesh with biological hole or Regenplate; Ridge—Form Mesh® ;
Non Resorbable Titanium
completely covered Frios® bone shields
Cytoplast® TXT-200
Dense PTFE.
Gore-tex®
Polytetrafluorethylene Expanded PTFE.
Non Resorbable NeoGen®
(PTFE) Dual textured PTFE.
Gore-Tex® Ti; NeoGen® Ti.
Titanium reinforced PTFE.
Reinforced and Cytoplast Ti-250®
OsseoGuard®
Cross linked type I collagen
Resorbable BioMend® ; OSSIX® PLUS
Cross Linked Cross-linked
(animal origin) MatrixDerm™; Osseo Guard Flex® ;
type I and type III
EZCure™
Type I collagen CollaTape® ; Tutodent®
Resorbable Type I and III collagen BioGide® ; botiss Jason®
Non-Cross Linked
(animal origin) Collagen with intermingled elastin Creos xenoprotect
Type I, III, IV, VI and other proteins DynaMatrix®

• Non-resorbable membranes are generally indicated in guided bone regeneration (GBR)

or in situations of bone deficiency. They are no longer used in periodontal regeneration
mainly because the introduction of minimal flaps does not allow the insertion of these
unwieldy barriers. Titanium reinforced membranes and polytetrafluorethylene are the
most common (Figures 5 and 6). Nowadays, new technologies and the introduction of
tissue engineering mean that the regenerative process is oriented towards the use of
resorbable materials, avoiding the need for a second surgical phase [51,52].
• Resorbable membranes are made from collagen, a natural substance that can be
resorbed (Figure 7). Several types are available, and these differ in resorption time. As
reported in Table 1, the fabrication of these membranes may or may not involve cross-
linking [53]. The cross-linking process aims to reinforce the chemical bonds among
the collagen fibers, and this results in a long resorption time. Collagen membranes
have a low risk of exposure in the oral cavity, but due to their low mechanical stability,
the use of bone substitutes or fillers is also required [42]. The use of membranes raises
the potential for complications such as exposure, which could reduce the regenerative
potential and allow the infiltration of bacteria and possible infection of the site [42].
 (GBR) or in situations of bone deficiency. They are no longer used in periodontal
regeneration mainly because the introduction of minimal flaps does not allow the
insertion of these unwieldy barriers. Titanium reinforced membranes and polytetra-
fluorethylene are the most common (Figures 5 and 6). Nowadays, new technologies
Encyclopedia 2021, 1 and the introduction of tissue engineering mean that the regenerative process is 92
oriented towards the use of resorbable materials, avoiding the need for a second
surgical phase [51,52].

Encyclopedia 2021, 1, FOR PEER REVIEW 6

Encyclopedia 2021, 1, FOR PEER REVIEW 6

Figure 5. Example of a non-resorbable Polytetrafluorethylene (PTFE) membrane.
Figure 5. Example of a non-resorbable Polytetrafluorethylene (PTFE) membrane.

Figure 6. Example of old periodontal non resorbable PTFE membranes, (A): wraparound shape for
large defects; (B): Interproximal shape for interproximal defects.

• Resorbable membranes are made from collagen, a natural substance that can be re-
sorbed (Figure 7). Several types are available, and these differ in resorption time. As
reported in Table 1, the fabrication of these membranes may or may not involve
cross-linking [53]. The cross-linking process aims to reinforce the chemical bonds
among the collagen fibers, and this results in a long resorption time. Collagen mem-
branes have a low risk of exposure in the oral cavity, but due to their low mechani-
cal stability, the use of bone substitutes or fillers is also required [42]. The use of
Figure 6. Exampleraises
of old periodontal non resorbable PTFE membranes, (A): wraparound shape for
Figuremembranes
6. Example of oldthe potential non
periodontal for complications
resorbable PTFEsuch as exposure,
membranes, which
(A): could shape
wraparound for
largereduce
defects;the
(B): Interproximal
regenerative shape and
potential for interproximal defects.of bacteria and possible
allow the infiltration
large defects; (B): Interproximal shape for interproximal defects.
infection of the site [42].
• Resorbable membranes are made from collagen, a natural substance that can be re-
sorbed (Figure 7). Several types are available, and these differ in resorption time. As
reported in Table 1, the fabrication of these membranes may or may not involve
cross-linking [53]. The cross-linking process aims to reinforce the chemical bonds
among the collagen fibers, and this results in a long resorption time. Collagen mem-
branes have a low risk of exposure in the oral cavity, but due to their low mechani-
cal stability, the use of bone substitutes or fillers is also required [42]. The use of
membranes raises the potential for complications such as exposure, which could
reduce the regenerative potential and allow the infiltration of bacteria and possible
infection of the site [42].

Figure 7. (A) Soft tissue side; (B) Internal tissue side of a collagen membrane.
Figure 7. (A) Soft tissue side; (B) Internal tissue side of a collagen membrane.
3.3. Biologics
According to the United States Food and Drug Administration (FDA), biologics are
a wide range of products, proteins, growth factors, or a complex combination of these
substances used to treat various diseases or to enhance the regenerative process, as peri-
Encyclopedia 2021, 1 93

3.3. Biologics
According to the United States Food and Drug Administration (FDA), biologics
are a wide range of products, proteins, growth factors, or a complex combination of
these substances used to treat various diseases or to enhance the regenerative process,
as periodontal regeneration, via the activation and stimulation of periodontal cells [54].
Enamel matrix derivative (EMD), recombinant human platelet-derived growth factor-BB
(PDGF—BB), and bone morphogenic proteins (BMP) are currently available on the market.
EMD is extracted from pigs and is treated to make it biocompatible and thus to reduce
adverse reactions. This material is unique because it is only sold as Emdogain® (Straumann
AG, Basel, Switzerland). Also, according to the literature, it is the only biomaterial that led
to the complete reformation of the periodontal ligament in a histological evaluation [55].
Several studies suggest the use of EMD alone or in combination with bone fillers [56]. The
first study to show the efficacy of this material was conducted by Heiji et al. in 1997, in
which EMD was compared to open flap debridement of intraosseous defects [57]. EMD
was associated with significant CAL gains and pocket depth reduction [57]. Another series
of studies compared EMD to GTR with comparable results [58]. Interesting data came from
a study by Cortellini et al. in which the use of EMD as an adjunct to minimally invasive
techniques such as MIST improved stability, minimizing the post-surgical phase [59].
In terms of CAL gains, no relevant differences were found between EMD + MIST and
MIST alone [59]. In summary, EMD showed comparable results to GTR; moreover, the
potential complications of GTR might indicate EMD as a more reliable material with
fewer complications and easy handling [60]. Nevertheless, the defect’s anatomy plays a
crucial role in the regenerative potential of this molecule. PDGF-BB is a growth factor
that is active in hard and soft tissue healing, enhancing cell proliferation, angiogenesis
and migration [61]. The disadvantage is in its handling, which requires the use of scaffold
and fillers [62]. Several studies have evaluated the use of this molecule as an adjunct to
Beta-tricalcium phosphate (B-TCP), EMD, and bone allograft, with positive results for EMD
and allograft [62]. BMP are proteins found in bone and showed bone regeneration in an
animal model [63]. The most studied forms of this type of molecule are BMP-2, BMP-6,
and BMP-12. Interesting data came from a study by Wikesjo et al. in a canine model,
where the use of BMP-12 showed a regenerated and well-oriented periodontal ligament
with newly formed bone and cementum [64]. On the other hand, complications associated
with the use of these molecules include possible ankylosis or root resorption [63]. BMP
and PDGF-BB are available in the United States but have not been approved for use in
Europe. Other biologics that have been used in periodontal regeneration are the blood
derivates, platelet rich fibrin (PRF) and its surrogates L-PRF and A-PRF, which showed
promising results in the regeneration of periodontal defects and furcations [65]. Several
in vitro studies analyzed the biocompatibility and the behavior of these materials in contact
with the fibroblast of the periodontal ligament and showed the activation of cytoplasmatic
extensions and an increase in cell volume [66]. Moreover, these biologics are natural and
enriched with growth factors such as platelet-derived growth factors (PDGF), transforming
growth factor β (TGF-β), vascular endothelial growth factor (VEGF), and insulin-like
growth factor-1 (ILGF-1) that influence cellular differentiation and proliferation [66]. On
the other hand, histological evidence regarding these types of biologics is still lacking.

3.4. Futures Biologics

Future potential biologics include several growth factors that have a specific function
and are in experimental phase II and III of randomized clinical trials in human and canine
studies. Protein 15 (P-15), osteogenic protein 1 (OP-1), parathormone (PTH), and anti-
sclerostin antibodies (SOST) are under investigation. As shown in Table 2, several growth
factors are already under investigation, but their use is always associated with a scaffold or
bone filler.
Encyclopedia 2021, 1 94

Table 2. Growth factors under investigation for periodontal regeneration.

Evidence for Periodontal

Growth Factors Biologic Function Phase of Investigation
Regeneration?
P-15 Improving cells adhesion FDA approved Yes [67]
Chemiotaxis of progenitor’s cells
RhPDGF-BB FDA approved Yes [68]
and angiogenesis stimulation
BMP-2 Osteogenic differentiation FDA approved Yes [69]
BMP-6 Osteogenesis enhancer Preclinical On dog [70]
BMP-12 Active on ligaments and tendons Preclinical On dog [64]
Fibroblast and endothelial
rhFGF2 FDA approved Yes [71]
proliferation
Increase mitogenesis and
OP-1 Preclinical On dog [63]
differentiation of osteoblast
SOST antibodies Antiresorption effect on bone FDA approved Yes [72]
PTH Anabolic effect on bone Clinical N/A
P-15: Protein15; RhPDGF-BB: recombinant human platelet-derived growth factor; BMP-2: bone morphogenic protein-2; BMP-6: bone
morphogenic protein-6; BMP-12: bone morphogenic protein-12; rhFGF2: recombinant human fibroblast growth factor-2; OP-1: osteogenic
protein-1; SOST antibodies: anti-sclerostin antibodies; PTH: parathormone.

3.5. Future Therapies

Therapies that are currently under development are based on the use of cells and
3D printing scaffolds [73]. Several articles have suggested the use of cell cultures in
periodontal regeneration but their high cost and the need to involve specialist laboratories
remain a crucial problem for dentists. Nevertheless, according to Trovato et al., the use of a
micrograft (a collagen membrane enriched with stem cells) has potential in the regenerative
process [74]. A recent review by Mummolo et al. suggested that micrografts in periodontal
and bone regeneration are a good alternative to GTR or to other biomaterials such as
bone substitutes [75]. However, they have some limitations due to the availability of
progenitor cells in the tissue sample used, and the selection of the right scaffold as a
carrier. Another promising therapy is related to the 3D printing technology; indeed, it is
starting to enter the oral regenerative field with tailored scaffolds that can be customized
for each type of defect. Rasperini et al. showed for the first time the possibility of using
a 3D printed resorbable scaffold for a large osseous defect. The material used was a
synthetic polymer enriched with recombinant human platelet derived growth factor BB
(rhPDGF-BB) [76]. The 3D printing process allows the customization of the biomaterial
respect to the defect type achieving a better handling and a tailored treatment. The possible
complications reported in this case report were several such as the wound dehiscence,
exposure and afterwards microbial contaminations. The most recent technique is the
connective tissue graft (CTG) wall technique, introduced to suggest the use of CTG as a
barrier in adjunct to EMD reducing gingival recession and in some cases the possible soft
tissue restoration [77]. The advantages of this technique are the use of connective tissue
as barrier preventing the exposure, reducing the complications and improving the soft
tissue response. Moreover, the CTG positioned coronally respect to the defect seems to
prevent the soft tissue collapsing. This technique according to the authors is reliable in
deep intrabony defects with the absence of buccal bone (Figure 8). A disadvantage is the
presence of a second surgical site on the palatal aspect for the CTG sampling and patient
discomfort during the healing period.
Encyclopedia 2021, 1 95
Encyclopedia 2021, 1, FOR PEER REVIEW 9

Figure
Figure 8.
8. Illustration
Illustration of
of the
the connective
connective tissue
tissue graft
graft (CTG)
(CTG) wall
wall technique
technique with
with the
the use
use of
of connective
connective tissue
tissue as
as barrier
barrier and
and
enamel matrix derivatives (EMD) as biologics.
enamel matrix derivatives (EMD) as biologics.

4. Conclusions
4. Conclusions
Periodontal regeneration is an approach involving constant evolution, techniques,
Periodontal regeneration is an approach involving constant evolution, techniques,
and biomaterials that are constantly being improved to achieve better performance. In
and biomaterials that are constantly being improved to achieve better performance. In
conclusion, it is a promising approach for periodontally compromised patients.
conclusion, it is a promising approach for periodontally compromised patients.
Author Contributions: Conceptualization, L.M.; methodology, L.M.; formal analysis, L.M.; inves-
Author Contributions: Conceptualization, L.M.; methodology, L.M.; formal analysis, L.M.; inves-
tigation, E.M.; resources, A.F.; data curation, L.M. and A.F.; writing—original draft preparation,
tigation, E.M.; resources, A.F.; data curation, L.M. and A.F.; writing—original draft preparation,
L.M.; writing—review and editing, E.M. and A.F.; visualization, A.F.; supervision, E.M.; project
L.M.; writing—review and editing, E.M. and A.F.; visualization, A.F.; supervision, E.M.; project
administration, E.M. All authors have read and agreed to the published version of the manuscript.
administration, E.M. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Funding: This research received no external funding.
Conflicts of Interest: The authors declare no conflict of interest.
Conflicts of Interest: The authors declare no conflict of interest.
Entry Link on the Encyclopedia Platform: https://encyclopedia.pub/7186.
Entry Link on the Encyclopedia Platform: https://encyclopedia.pub/7186.
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